Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTVCRXEZ)

• DOT Name: Protein phosphatase 1 regulatory subunit 3B (PPP1R3B)
• Synonyms: Hepatic glycogen-targeting protein phosphatase 1 regulatory subunit GL; Protein phosphatase 1 regulatory subunit 4; PP1 subunit R4; Protein phosphatase 1 subunit GL; PTG
• Gene Name: PPP1R3B
• Related Disease:
  Advanced cancer
  Alzheimer disease
  Arteriosclerosis
  Atherosclerosis
  Breast cancer
  Breast carcinoma
  Depression
  Head and neck cancer
  Head and neck carcinoma
  Lafora disease
  Maturity-onset diabetes of the young
  Non-alcoholic fatty liver disease
  Non-insulin dependent diabetes
  Post-traumatic stress disorder
  Thrombophilia
  Type-1/2 diabetes
  Melanoma
  Neoplasm
  Obesity
  Fatty liver disease
• UniProt ID: PPR3B_HUMAN
• PDB ID: 2EEF; 5ZT0
• Pfam ID: PF03370
• Sequence:
  MMAVDIEYRYNCMAPSLRQERFAFKISPKPSKPLRPCIQLSSKNEASGMVAPAVQEKKVK
  KRVSFADNQGLALTMVKVFSEFDDPLDMPFNITELLDNIVSLTTAESESFVLDFSQPSAD
  YLDFRNRLQADHVCLENCVLKDKAIAGTVKVQNLAFEKTVKIRMTFDTWKSYTDFPCQYV
  KDTYAGSDRDTFSFDISLPEKIQSYERMEFAVYYECNGQTYWDSNRGKNYRIIRAELKST
  QGMTKPHSGPDLGISFDQFGSPRCSYGLFPEWPSYLGYEKLGPYY
• Function: Acts as a glycogen-targeting subunit for phosphatase PP1. Facilitates interaction of the PP1 with enzymes of the glycogen metabolism and regulates its activity. Suppresses the rate at which PP1 dephosphorylates (inactivates) glycogen phosphorylase and enhances the rate at which it activates glycogen synthase and therefore limits glycogen breakdown. Its activity is inhibited by PYGL, resulting in inhibition of the glycogen synthase and glycogen phosphorylase phosphatase activities of PP1. Dramatically increases basal and insulin-stimulated glycogen synthesis upon overexpression in hepatocytes.
• Tissue Specificity: Highly expressed in the liver and, at lower levels, in skeletal muscle, including in vastus lateralis, gastrocnemius and soleus (at protein level). Highest mRNA levels are observed in skeletal muscle, and only moderate levels in liver and heart. Weak expression in placenta and lung.
• KEGG Pathway:
  Insulin sig.ling pathway (hsa04910)
  Insulin resistance (hsa04931)

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Genetic Variation	[2]
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[3]
Atherosclerosis	DISMN9J3	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Depression	DIS3XJ69	Strong	Biomarker	[5]
Head and neck cancer	DISBPSQZ	Strong	Biomarker	[6]
Head and neck carcinoma	DISOU1DS	Strong	Biomarker	[6]
Lafora disease	DIS83JHH	Strong	Genetic Variation	[7]
Maturity-onset diabetes of the young	DISG75M5	Strong	Genetic Variation	[8]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Genetic Variation	[9]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Genetic Variation	[8]
Post-traumatic stress disorder	DISHL1EY	Strong	Biomarker	[4]
Thrombophilia	DISQR7U7	Strong	Genetic Variation	[10]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[11]
Melanoma	DIS1RRCY	moderate	Biomarker	[12]
Neoplasm	DISZKGEW	moderate	Biomarker	[12]
Obesity	DIS47Y1K	moderate	Genetic Variation	[13]
Fatty liver disease	DIS485QZ	Limited	Genetic Variation	[14]

20 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Protein phosphatase 1 regulatory subunit 3B (PPP1R3B).	[15]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Protein phosphatase 1 regulatory subunit 3B (PPP1R3B).	[16]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Protein phosphatase 1 regulatory subunit 3B (PPP1R3B).	[17]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Protein phosphatase 1 regulatory subunit 3B (PPP1R3B).	[18]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Protein phosphatase 1 regulatory subunit 3B (PPP1R3B).	[19]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Protein phosphatase 1 regulatory subunit 3B (PPP1R3B).	[16]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Protein phosphatase 1 regulatory subunit 3B (PPP1R3B).	[20]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Protein phosphatase 1 regulatory subunit 3B (PPP1R3B).	[21]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Protein phosphatase 1 regulatory subunit 3B (PPP1R3B).	[22]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Protein phosphatase 1 regulatory subunit 3B (PPP1R3B).	[21]
Niclosamide	DMJAGXQ	Approved	Niclosamide decreases the expression of Protein phosphatase 1 regulatory subunit 3B (PPP1R3B).	[23]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Protein phosphatase 1 regulatory subunit 3B (PPP1R3B).	[21]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Protein phosphatase 1 regulatory subunit 3B (PPP1R3B).	[21]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of Protein phosphatase 1 regulatory subunit 3B (PPP1R3B).	[24]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Protein phosphatase 1 regulatory subunit 3B (PPP1R3B).	[25]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Protein phosphatase 1 regulatory subunit 3B (PPP1R3B).	[26]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Protein phosphatase 1 regulatory subunit 3B (PPP1R3B).	[27]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Protein phosphatase 1 regulatory subunit 3B (PPP1R3B).	[28]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Protein phosphatase 1 regulatory subunit 3B (PPP1R3B).	[29]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of Protein phosphatase 1 regulatory subunit 3B (PPP1R3B).	[30]

References

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• [9] American Ancestry Is a Risk Factor for Suspected Nonalcoholic Fatty Liver Disease in Hispanic/Latino Adults.Clin Gastroenterol Hepatol. 2019 Oct;17(11):2301-2309. doi: 10.1016/j.cgh.2019.02.007. Epub 2019 Feb 8.
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• [13] Distribution of local ancestry and evidence of adaptation in admixed populations.Sci Rep. 2019 Sep 25;9(1):13900. doi: 10.1038/s41598-019-50362-2.
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• [18] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [19] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [20] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
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• [22] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [23] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [24] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [25] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [26] Loss of TRIM33 causes resistance to BET bromodomain inhibitors through MYC- and TGF-beta-dependent mechanisms. Proc Natl Acad Sci U S A. 2016 Aug 2;113(31):E4558-66.
• [27] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [28] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [29] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [30] Effects of nickel treatment on H3K4 trimethylation and gene expression. PLoS One. 2011 Mar 24;6(3):e17728. doi: 10.1371/journal.pone.0017728.